Ch 7 - Major histocompatibility complex and antigen presentation

class 1 vs class 2 MHC

class 1 - all nucleated cells, present intracellular entities (ex viral proteins), present to CD8, cytokines/infections/disease change expression, TAP, proteasome

class 2 - on APCs, present extracellular Ag, present to CD4, cytokines/PAMPS upregulate expression, invariant chain/DM, endosomal and lysosomal proteases

structure and function of MHC molecules

both - Ig superfamily, have peptide binding groove where its loaded

class 1 - large alpha chain, small beta2 chain, peptide binding groove closed at each end

class 2 - alpha and beta chain (no size diff), peptide binding groove open at each end

MHC peptide interaction

class 1 - peptides bound by MCH 1 8-10 amino acids, anchor residues are specific amino acids at key locations, binding strong at ends (can arch in middle)

class 2 - peptides bound by MCH 1 13-18 amino acids, central core of amino acids determines binding ability (no anchor residues), can overhang, held at constant elevation (no arch)

general organization and inheritance of MHC

every vertebrate studied has MHC, class 1 and class 2 both exhibit polymorphism in peptide binding region (allows lots of peptides to be bound), lots of allelic variants have been identified, a given MHC can bind numerous peptide/some peptides can bind several MHC = promiscuous

haplotype

MHC genes are polymorphic (multiple alleles), some individual MHC genes are so close together that their inheritance is linked, individuals inherit all alleles encoded by these genes as a set

errors in inheritance of haplotypes generate polymorphism (ex genes misalign during meiosis/recombination)

MHC genes in human/mice

mice: chromosome 17, H-2 complex, class 1=K, class 2=IA, IE (ex H-2 K is MHC class 1)

human: chromosome 6, HLA complex, class 1=B,C,A, class 2=DP,DQ,DR (ex HLA DP is class 2)

how are MHC alleles expressed

codominantly (both maternal and paternal gene products expressed at same time in the same cell

types of mice for research

syngeneic - inbred mice, identical at all loci

congenic - genetically identical except at a single region

allogeneic - completely different

human inheritance histocompatibilty

when mother and father have different haplotypes there is a 1 in 4 chain siblings will inherit same haplotypes and be histocompatible, no offspring will be fully histocompatible with parents

types of grafts

autograft - piece moved to diff spot on same person

isograft - genetically identical/syngeneic

allograft - genetically different (risk of rejection)

xenograft - one type of animal to another

direct vs indirect Ag presentation

direct - donor APC, host TC

indirect - host APC (with donor peptide), host TC

this is important for transplantation/rejection, even if you immunosuppress peptide can still be picked up

MHC is polygenic

multiple genes with the same function but slightly different structures

loss of MHC polymorphism

susceptibility to viral diseases, specifically seen in cat populations where breeding is limited

MHC presents both intracellular and extracellular Ag

class 1 presents intracellular, this includes self proteins, provides a way of "checking" that cells are self and healthy, can show which cells have been infected/abnormal

class 2 presents extracellular, more restricted, found on cells involved in immune responses, helps direct responses against threats

MHC expression patterns

MHC 1- expressed constitutively unless altered self state (some neurons and sperm lack MHC 1), expression is lowest in fibroblasts/muscle cells/liver/hepatocytes (explains success of liver transplants)

MHC 2 - expression in flux based on cell development/if cytokine present (level of activation)

professional antigen presenting cells (pAPC)

cells that can express MHC 2 and deliver a costimulatory (second) signal to TC (TC need 2 signals to be fully functional); includes DC, macrophage, BC

nonprofessional APCs

can be induced to express MHC 2 and/or costimulatory signals under certain conditions, includes mast cells, basophils, eosinophils, ILC3

self-MHC restriction

refers to dual specificity of TC for self MHC as well as foreign Ag; MHC haplotype of APC and TC must match, Ag must be processed (experiment blocking processing demonstrated this)

experiments to demonstrate self-MHC restriction

class 2 - used 2 different strains, made one good at Ag presenting and one good at recognizing, introduced both strains to each other, if the strains didn't match presentation didn't work

class 1 - used cells that should drive a CTL response, only worked when the strain matched

endogenous pathway of Ag presentation

ubiquitin proteins tag intracellular proteins for degradation, tagged proteins fed into proteasomes, immunoproteasome cleaves proteins into fragments to pair with MHC molecules, peptides transported to rough ER, TAP moleucles in ER move fragments, MCH class 1 molecules wait in ER, chaperones aid peptide/MHC 1 assembly, molecules help fold/trim peptides to correct size for MHC grooves

exogenous pathway of Ag presentation

particles are taken within endosomes, endosomes fuse with lysosome to degrade contents, MHC 2 are produced and exported from ER in vesicles, invariant chain prevents peptides from binding to groove too early and directs MCH 2 vesicles to the peptide compartment, CLIP blocks binding so you don't load to early, HLA-DM exchanges CLIP for peptide (MHC 2 assembly)

cross presentation

pathway in some pAPCs where Ag is redirected from exogenous to endogenous pathway, internalized Ag that would normally go through MHC 2 pathway are redirected to MHC 1, DC are only AP to exhibit this activity

presentation of non peptide Ag

CD1 family molecules share characteristics of both MHC 1 and 2, great at presenting glycolipids